Regulatory circuits controlling vascular cell calcification

Abstract

Vascular calcification is a common feature of chronic kidney disease, cardiovascular disease, and aging. Such abnormal calcium deposition occurs in medial and/or intimal layers of blood vessels as well as in cardiac valves. Once considered a passive and inconsequential finding, the presence of calcium deposits in the vasculature is widely accepted as a predictor of increased morbidity and mortality. Recognition of the importance of vascular calcification in health is driving research into mechanisms that govern its development, progression, and regression. Diverse, but highly interconnected factors, have been implicated, including disturbances in lipid metabolism, oxidative stress, inflammatory cytokines, and mineral and hormonal balances, which can lead to formation of osteoblast-like cells in the artery wall. A tight balance of procalcific and anticalcific regulators dictates the extent of disease. In this review, we focus on the main regulatory circuits modulating vascular cell calcification.

Fig. 1

Schematic diagram of regulation of vascular cell calcification by systemic and local factors, including activators such as oxylipids (produced under increased oxidant stress), cytokines (produced by lipid-laden macrophages), hormones, calcium/phosphate (Ca/Pi) nanocrystals, and inhibitors

Fig. 2

Types of vascular calcification: a intimal atherosclerotic calcification (arrow) of human femoral artery by von Kossa staining; b medial calcification (arrows) of murine artery by hematoxylin and eosin (H&E) staining, magnification 100×; and c calcified cartilaginous metaplasia (arrows) of murine aortic root by hematoxylin and eosin (top) and von Kossa (bottom) staining, magnification 100×

Fig. 3

In vitro matrix mineralization (arrow) of murine VSMC in response to inorganic phosphate treatment indicated by calcein (green, calcium mineral), Alexa Fluor 568 conjugated to phalloidin (red, actin network), and DAPI (blue, nuclei), magnification 100×